U.S. Concern Over Compounders Predates Outbreak of Meningitis

Vials of a steroid made by the New England Compounding Center, linked to meningitis cases.Credit
Minnesota Department of Health, via Associated Press

A year before people began dying of meningitis caused by a tainted drug from a compounding pharmacy in Massachusetts, the Food and Drug Administration worried that compounders across the country might be selling another substandard drug, one possibly made with unapproved Chinese ingredients.

But when the F.D.A. began seeking samples to test, the trade group representing compounding pharmacists went on the offensive. Instead of encouraging members to help the agency determine if the injectable drug, used to reduce the risk of premature birth, was substandard, the group tutored pharmacists on how to sidestep requests.

In an e-mail to members, the International Academy of Compounding Pharmacists suggested that they respond to any request for samples by saying, “We do not compound or distribute ‘samples’ of any of our prescription medications to anyone.” And if a compounded drug was on the premises, the trade group added, a pharmacist should say it was awaiting pickup by a patient.

A spokesman for the trade group said the instructions were intended to guard against unauthorized release of samples to corporate competitors and not to hinder the F.D.A. investigation. But the memo is emblematic of the industry’s frequent and often successful attempts to fend off regulators at a time when concerns are growing about the quality of compounded drugs and the uncertain provenance of their ingredients, some of which originate in China and flow through various repackagers and middlemen with little scrutiny, according to interviews with health experts and government records.

Drugs made by compounders — who mix or alter ingredients to create customized medicine for a specific patient — are rarely tested, unless someone is harmed or a complaint is filed. But in the only two states that randomly test compounded drugs, Texas and Missouri, significant problems have surfaced.

In Texas, a hub of compounding pharmacies, random tests by the state’s pharmacy board over the last several years found that as many as one in four compounded drugs was either too weak or too strong. The testing results are just slightly better in Missouri. Potency varied by as much as 300 percent in the Missouri tests.

And records of F.D.A. drug seizures at United States borders, as well as several criminal cases, point to a link between drug compounders and Chinese manufacturers, some not registered with the F.D.A. Records analyzed by The New York Times show that in 62 cases over the last decade, the F.D.A. blocked the importation of drugs for use in compounding; nearly half were from China, one of the largest producers of raw pharmaceutical ingredients, where many manufacturers operate outside the regulatory net.

The F.D.A. said on Friday that investigators did not believe that original ingredients used by the Massachusetts pharmacy, the New England Compounding Center in Framingham, were the source of the crisis unfolding in 16 states, where at least 297 people have contracted meningitis and 23 have died.

Beyond the Massachusetts case, though, United States authorities have expressed concern that compounders, far less stringently regulated than commercial drug makers, have been using ingredients manufactured overseas in factories not approved by the F.D.A.

Last year, the F.D.A. issued an import warning after noticing that “a large increase” in unapproved human growth hormone, manufactured overseas, was being offered to compounding pharmacies.

In March, an upstate New York company, Medisca, which sells ingredients to compounders, forfeited $1.7 million from the unlawful sale of human growth hormone supplied by an unapproved Chinese drug maker. Two other compounding pharmacies were also found in recent years to have illegally sold anabolic steroids and human growth hormone made in China.

As companies increasingly buy raw materials from foreign sources — about 80 percent of active pharmaceutical ingredients in products sold in the United States are from overseas — regulators are struggling to keep up.

Modern supply chains are a maze of importers, repackagers and dealers. But while large drug companies, bound by F.D.A. rules, must keep meticulous track of who has handled their raw materials, compounding pharmacies are not bound by those guidelines, even though some have grown so large that they resemble commercial manufacturers.

Michael Chappell, a former high-ranking F.D.A. official who helped to oversee the agency’s regulatory policies, said federal officials have had difficulty at times getting answers to questions about where compounders bought their ingredients.

“Is it being repackaged in the back of a ’57 Buick in a parking lot somewhere?” Mr. Chappell asked. “The answer was always, ‘We get them from our suppliers.’ But what do you know about that supplier? Who makes the original chemical?”

Photo

A sample of one of the fungi species diagnosed in the outbreak.Credit
Harrison Mcclary/Reuters

Some compounding pharmacies have taken advantage of the legal no-man’s land in regulation. The F.D.A. can inspect them and issue warnings, but the agency says states have ultimate jurisdiction.

“You can ask a question, but does a company have to answer you?” said Robert Coleman, who was an F.D.A. investigator for three decades and is now a consultant based in Atlanta. “That’s up for debate. It always made me wonder as an investigator, ‘Why don’t you want to tell me that? Is there some problem?’ ”

The F.D.A. has authority if it decides that a compounding pharmacy is manufacturing, and not simply mixing drugs for individual patients. But to make that determination, the agency has to look at a pharmacy’s records to see its volume, and pharmacies argue that the law does not require them to produce those records.

“There is some legal dispute about our ability to look at records and pharmacies and it is the records that help us determine whether a pharmacy is acting as a pharmacy or as a manufacturer,” Deborah M. Autor, the F.D.A.’s deputy commissioner for global regulatory operations and policy, said in a phone call with journalists. Some consumer advocates say that the F.D.A. has the authority to investigate compounding pharmacies but often chooses not to.

Unlike commercial drug manufacturers, compounding pharmacies are not bound by the agency’s so-called good manufacturing practices, which require companies to report instances when their medicine might have harmed patients. Usually the F.D.A. learns about such cases only through the news media or voluntary reporting.

There have been virtually no federal efforts to quantify the problem of large-scale compounding pharmacies or their rapid growth, but the F.D.A. has occasionally taken a limited look at the quality of their drugs. In 2001, the agency looked at samples of compounded products from 12 different pharmacies and found that a third of the products failed one or more standard quality tests, mostly having to do with potency. A similar F.D.A. survey in 2006 found the failure rate about the same.

After a pharmacist in Kansas City, Mo., pleaded guilty to watering down chemotherapy drugs, the Missouri Board of Pharmacy began in 2006 randomly sampling compounded drugs. In 2008, one in four samples failed a potency test. The failure rate dropped to 15 percent in 2010, the most recent year available.

The Texas State Board of Pharmacy started its own random testing program after seeing what Missouri had done. That state’s failure rate has generally hovered between 20 percent and 25 percent. “If you take a drug, you should expect to get the amount of drug listed on the bottle,” said Gay Dodson, the board’s executive director.

In April, a compounding pharmacy in Dallas, ApotheCure Inc., and its owner, pleaded guilty in federal court to two misdemeanors for shipping a misbranded drug that led to the deaths of three people in the Pacific Northwest. Subsequent testing by the F.D.A. found that some vials were superpotent, containing 640 percent of the drug listed on the label, while others were subpotent.

K V Pharmaceuticals, a drug company in St. Louis, did not rely on the government to assess the quality of compounded drugs that competed with its F.D.A.-approved product, Makena, used to reduce the risk of premature birth. K V hired a corporate intelligence firm to obtain and test samples of the compounded version, 17P, for potency and purity.

In January, the company’s researchers published their findings, alleging that 80 percent of the drug did not meet purity specifications. Michael J. Jozwiakowski, a co-author of the study, said the only companies they could find that manufactured the active pharmaceutical ingredient, available to compounders, were Chinese companies not registered with the F.D.A. One sample contained nothing but glucose.

When the F.D.A. was given the data last fall, the agency decided to take its own samples of the compounded version, prompting the International Academy of Compounding Pharmacists, the trade organization, to offer its members advice on how to respond to F.D.A. requests, in an e-mailed member alert titled, “F.D.A. Calling Compounders about 17-P.”

The trade group spokesman, David Miller, said the alert, despite its title, was intended to defend against data collectors from K V Pharmaceuticals, who member pharmacies said had been calling them asking for samples.

“There was no evidence that any of the calls pharmacies received were coming from a genuine governmental official,” Mr. Miller said. “Regulators do not ‘call around’ asking for information. They come to a pharmacy with an official inspection form.”

He denied that the alert contained language instructing members not to cooperate with federal regulators. “There is not one word in that document that says do not comply with a regulator,” he said.

Dr. Michael Carome, deputy director of Public Citizen’s Health Research Group, a nonprofit consumer organization, said the group’s advice to members should have been to cooperate fully and answer all their questions. Instead, Dr. Carome said, the group suggested answers “for which the implicit, if not explicit message was to stonewall and obstruct” the F.D.A.’s attempt to assess the quality of the compounded drug.

The F.D.A. said in June that after obtaining and testing 13 samples of the compounded drug, it had found no significant quality problems. K V Pharmaceuticals filed for bankruptcy this year, and is suing the F.D.A.

Sarah Cohen contributed reporting.

A version of this article appears in print on October 23, 2012, on page A1 of the New York edition with the headline: U.S. Concern Over Compounders Predates Outbreak of Meningitis. Order Reprints|Today's Paper|Subscribe